Research Article Curr Trends Biomedical Eng & Biosci Volume 17 Issue 5 - January 2019 Copyright © All rights are reserved by Idoko A DOI: 10.19080/CTBEB.2019.17.555971 Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of Stem bark of indica in Aluminium Chloride induced Toxicity in Albino Wistar rats

Idoko A1*, Emmanuel UG1, Yakubu OE3, Ugwudike PO1 and Patricia NA2 1Department of Biochemistry, Caritas University, Nigeria 2Department of Microbiology, University of Ibadan, Nigeria 3Department of Biochemistry, Federal University Wukari, Nigeria Submission: November 22, 2018; Published: January 17, 2019 *Corresponding author: Idoko A, Department of Biochemistry, Faculty of Natural Sciences, Caritas University, Amorji – Nike, P.M.B. 01784, Enugu, Nigeria

Abstract

Herbal therapies have been used to manage liver diseases resulting from hepatotoxicity and hyperglycemia. The study investigated the hepatoprotective and gluco-stabilizing abilities of ethanol extracts of stem bark of Flacourtia indica in albino Wistar rats. Thirty-one rats of mixed

E (20 rats). At phase 1, group A (negative control) was made up of 3 rats administered no AlCl3 and no leaf extracts while groups B (positive control),sex, weighing C and 165-285g D (test) made were of used 4 rats and each, divided administered into five groups 260mg/kg of A bodyto E. Acuteweight toxicity AlCl3 only, study for of 7 the days. ’s At phase stem 2, bark groups was C conducted and D were on treated group with stem bark extract of Flacourtia indica for 7 days. Activities of Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase,

concentrations of Bilirubin, Albumin, Total protein and blood glucose were assayed with histopathological study on euthanized rats’ liver.

HistopathologyResults of phase results 1 showedin phase2 significant showed regeneration(p˂0.05) increase and healing in the liver of damaged function hepatocytes enzyme and of blood phase1. glucose In conclusion, after induction the liver with injury AlCl3 induced compared by with (phase 2) values of liver function enzyme and blood glucose with significant (p˂0.05) decrease after treatment with stem bark extract. AlCl3 was found to be effectively managed by the treatment with Flacourtia indica

oxygen . ’s ethanol stem bark extracts, with blood glucose stabilized. This could be as a result of the antioxidants and phytochemical contents of the plant, with diver’s potency to scavenge free radicals and reactive Keyword: Flacourtia indica; Gluco-stabilizer; Hepatic function; Hepatoprotective; Hyperglycemia; Stem bark

Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; WHO: World Health Organization; BIL: Bilirubin; TP: Total Protein

Introduction of glycogen), iron and vitamins such as vitamins A, folate (B9), The liver, a reddish – brown heaviest and largest internal B12 and D [6]. Enzymes such as alanine aminotransferase (ALT), organ weighs about 1.5 – 1.6 kg in an adult male and is about Aspartate aminotransferase (AST) and hormones are synthesized the size of an American football [1]. It is located behind the by the liver [7]. However, the liver is adversely affected by ribcage on the upper right side of the abdomen and is divided overloaded toxic substances, resulting in hepatotoxicity [8]. into four lobes with multiple lobes containing hepatic cells (hepatocytes). A normal liver enjoys an adequate blood supply Hepatotoxicity is implicated with chemical induced liver and ability to regenerate its own tissues within few days [2]. The damage resulting in chronic and acute liver diseases. Over liver is known to perform over 500 functions in the body which 800 chemicals causing hepatic injuries abounds. They include

ibuprofen, acetaminophen or paracetamol, naproxen and aspirin include detoxification, excretion, digestion, metabolism, storage to the body such as drugs, chemicals, heavy metals, alcohol and drugs used to suppress pain and reduce inflammation such as and homeostasis. It detoxifies harmful substances that are toxic pesticides [3]. The liver excretes toxic chemical substances in and laboratory chemicals such as Aluminum trichloride AlCl (Non-Steroidal Anti-inflammatory Drugs), alcohol, industrial3 the bile as well as xenobiotics, hormones and other by-products and carbon tetrachloride CCl4 and natural toxins such viruses,

[4]. The liver plays a major role in homoeostasis stability of trace 3 has demonstrated elements [5]. The liver is a major store house of glucose (in form high potency in exerting hepatotocity, the mechanism by which aspergillus flavus [6,9,10]. Meanwhile, AlCl

Curr Trends Biomedical Eng & Biosci 17(8): CTBEB.MS.ID.555971 (2019) 0072 Current Trends in Biomedical Engineering & Biosciences

AlCl3 exert its injury on the liver is not yet clear [9]. These induced higher than the value of blood glucose. Hypoglycemia implies a toxic chemicals in the hepatic tissue, render the liver disease with decrease in blood glucose concentration from the normal and malfunction including hepatitis, liver cancers, fatty liver, primary hyperglycemia is an increase in blood glucose concentration from biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, the normal [29,30]. have been reported to have herbal ability in reducing high glucose concentration, not necessarily earth is made up of about 8.13% of aluminium. The metal has got causing an unhealthy hypoglycemia, but attempting to stabilize hyperoxaluria and oxalosis and Wilson’s disease [11,12]. The wide utilization, therefore increasing the chances of exposure into blood glucose level in albino wistar rats [30]. Thus, in view of the body through the intestinal tract and the lung. It is a used in these, it became imperative to investigate the hepatocurative and manufacturing cosmetics such as roll-on and deodorant, cooking gluco-stabilizing effects of stem bark of Flacourtia indica using utensils, food additives and drugs such as antacids. In water ethanol solvent extraction in order to ascertain the previous claim and establish new fact. purification,The practice aluminium of traditional salts are medicine, also used using [13]. plants and plants Materials and Methods products for the treatment of ailments is an age long practice. Chemicals Several medicinal plants with their herbal functions have been Aluminium trichloride AlCl was purchased from BDH discovered and more are still be researched on [14]. Medicinal 3 plants have been found to possess several activities such as Laboratories/Chemicals Ltd, Poole, England. Kits used for the hepatoprotective, nephroprotective, antimicrobial, anticancer, liver function assay were obtained from Randox Laboratories Ltd, 55 Diamond Road, Crumlin, country Antrim, BT29 4QY, United hypoglycemia, heamatinic and antioxidant activity [15-17]. These Kingdom. They include; Bilirubin (BIL), Alanine Aminotransferase anti-inflammatory, hypoglycemic, antihypercholesterolemia, (ALT), Aspartate Aminotransferase (AST), Albumin (ALB), Total impacts of medicinal plants on man and animals are not farfetched Protein (TP). All other chemicals used are pure and of analytical beneficial therapeutic properties and efficient pharmacological from the numerous bioactive compounds they contain [18]. The grade. availability of herbal alternatives for the management of liver Collection and Preparation of Plant Samples disease and other ailments is been encourage by world health Fresh plant materials of Flacourtia indica were collected from around Emene jurisdiction in Enugu state, safety of use, cheap to purchase and accessible for patronage [19]. (Governor’s plum) organization (WHO) to be better developed for improved efficacy, Nigeria. The required plant stem bark was authenticated and a Flacourtia india is a wide spread medicinal plant, of voucher number of PSB/109-12. A was given by Mr. Okafor, C.U., family, tribe of , genus of Flacourtia and specie of a botanist in plant tissue culture and biotechnology department, Faculty of Biological Science, University of Nigeria, Nsukka. The or Katai in India, Cilimu in China and in Nigeria: it is called Akpuru plant extract was prepared by pilling the bark from the stem of Indica [20, 21]. It is known as Governor’s plum in English, kondai in Igbo, Isada in Hausa and Iyeye in Yuroba [22]. The plant is the plant and cut into pieces for easy air drying. The dried samples tropical specie with a natural geographical occurrence in Africa were ground into powder using an electric grinder. The powdered and Asia. Predominantly, Flacourtia india is said to be a native to parts were soaked in ethanol and allowed to stay for 48 hours at both Africa and East Asia [23]. Flacourtia indica is a bushy small like , having a spiny, erect, rough, strong stem bark, the samples were then taken and evaporated to dryness using room temperature after which they were filtered. After filtration, that extend with branches. It spines branched and spread up to water bath at 80oc. The evaporated extracts were reconstituted 12cm long and to a maximum height of about 15cm (50 feet) [22]. with distilled water relative to the weight of the evaporated extract. Several pharmacological abilities of Flacourtia indica have been The volumes of the extracts to be administered were calculated exploited with the whole plant, leaf, seed, fruit, stem, bark and root. according to the body weight of the rats using the formula: These include hepatoprotection against AlCl , paracetamol and 3 weight of rats ( kg) x Concentration Dose ( mg / kg) CCl induced hepatic damage [9,24], anti-diabetic, anti-anxiety, Volume to be administered ( ml) = 4 Concentration of the extract( mg / ml) antimicrobial, anti-malaria, anti-asthmatic, diuretic, antioxidant, Collection and preparation of blood sample 27]. The plant has been reported by previous researchers analgesic/anti-inflammatory and anti-hyperlipidemia [18,25- Three milliliter (3mls) of blood was collected from the rats in their phytochemical analysis to contain several bioactive by capillary pressure insertion into the side of the eye using capillary tubes into a plain bottle, for the collection of serum used carbohydrate, Coumarin Glycosides [28]. compounds, including phenolic compounds, flavonoids, saponins, for biochemical assay (liver function test). The samples in bottles Blood glucose concentration is an important index handled were stored at room temperature. by the liver in monitoring and stabilizing blood glucose levels. In Acute Oral Toxicity (LD ) Study post absorptive state, the fasting blood glucose concentration of 50 Twenty (20) rats were used for oral acute toxicity study (LD ) a healthy (normal) individual is 70 – 100mg/dl (4.5-5.5mmol/l). 50 However, after eating a carbohydrate meal, the level of blood of the plant. The acute toxicity study of ethanol stem bark extract glucose may rise to 120-140mg/dl. It is generally established of Flacourtia Indica was evaluated in two phases as described that the value for plasma concentration is about 15% slightly by [31]. In the 1st phase, doses of 10mg/kg, 100mg/kg, and

How to cite this article: Idoko A, Emmanuel U, Yakubu O, Ugwudike P, Patricia N. Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of 0073 Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats. Curr Trends Biomedical Eng & Biosci. 2019; 17(5): 555971. DOI: 10.19080/CTBEB.2019.17.555971. Current Trends in Biomedical Engineering & Biosciences

1000mg/kg were administered to 3 rats each. The body weight of Liver Function Assay rat was noted before and after extract administration. Single dose After collection of blood sample from rats serum was of ethanol extract was administered orally and observed from the collected by clot retraction. Serum ALT, AST, ALP, Albumin, Total time of administration, for toxic symptoms, such as behavioral protein and Bilirubin were assayed with the use of kits from changes, loco-motion, convulsion and mortality, then overnight Randox Laboratories Ltd, 55 Diamond Road, crumlin, country and finally for a time period of five days. In the absence of procedure. kg, 3500mg/kg and 5000mg/kg were then administered on 1 rat Antrim, BT29 4QY, United Kingdom, following the manufacturer’s mortality in the first phase, higher doses of 1500mg/kg, 2500mg/ each of which one mortality was observed in the 2nd phase of Histopathological Studies the experiment at 3500mg/kg body weight. LD50, the amount or lethal dose of materials given all at once, which causes the death The selected models were sacrificed and dissected after of 50% of a group of test animals was calculated with the formula of 0.9% of formalin solution in plain tissue bottles. The tissues below; which the liver organs were excised and fixed in a buffer medium

= × with hemotoxin and eosin, the sections were examined and LD50 Min. Conc . that caused death Max . conc . that result to no death were embedded in paraffin, solid section was cut 5um and stained analyzed by the distant Specialist of histopathology, University Study Animals of Nigeria under high microscopy instrumentation having Albino Wistar rats of 165-285g weight, of either sex were photomicrographic attachment. obtained from university of Nigeria Nsukka. Animals were housed Statistical analysis house of natural sciences, Caritas University, Amorji – Nike Enugu. Results were expressed as mean ± standard deviation and at an ambient temperature and relative humidity in the animals’ The rats were allowed to acclimatize for one week prior to the analyzed using one-way ANOVA (analysis of variance, p value

instat 3 software version 3.05 by graph pad Inc. was employed feed and clean water within the period the acclimatization. The (p<0.05) was considered significant. A component of graph pad experiment and had access to standardized pelletized finisher [34]. investigation of experimental pain in conscious animals were principle of laboratory animals’ care and ethical guidelines for Results followed respectively [32,33]. Acute toxicity results Experimental Design The oral administration of ethanol extract of F. indica stem bark resulted in behaviour changes and mortality up to the dose (35) Wistar albino rats were used, divided into A, B, C, D and E as of 3500 mg/kg body weight at the second phase. Though, the Experimental design was carried out in two phases thirty five follows; at phase 1, LD50 of F. indica ethanol stem bark extract was calculated to be 4183mg/kg (higher than 3500 mg/kg). Table 1 shows the result Group A: Control (negative control) consist of 4 rats, no of the acute toxicity in phase 1 and 2. The liver function test of Aluminum chloride (AlCl3 were administered. rats after induction with 260mg AlCl3, for liver injury is shown in Group B: Test control (positive control) consist of four (4) rats, were administered orally with 260mg of Aluminum BIL, ALP, ALT and AST of control compared to test control and test Table 2. A significant (p<0.05) increase was observed in TP, ALB, chloride (AlCl3) without extract given. groups. Group C: Consist of four (4) rats, were orally Table 1: Phase I and II Acute Toxicity of Ethanol stem bark extracts of Flacourtia Indica. administered with 260mg/kg body weight of rats. Dose (mg/kg) & Mortality Dose (mg/kg) & Mortality Group D: Consist of four (4) rats were orally administered with 260mg/kg body weight of rats. At phase 2, groups C and D Phase 1 Dose Mortality Phase 2 Dose Mortality were treated with ethanol stem bark as follows; 10 0/3 1500 0/1

Group C: Consist of four (3) rats, were treated with stem 100 0/3 2500 0/1 bark extracts of 500mg/kg body weight of rats. 1000 0/3 3500 1-Jan Group D: Consist of four (3) rats were treated with stem 5000 0/1 bark extract of 700mg/kg body weight of rats. Table 3 shows liver function indices of rats administered var- At the end of phase 1 and 2, one rat from each group was - ious dose of stem bark (500mg and 700mg) extract of flacourtial chloroform and liver removed for histopathology study. in all parameters assayed in the test groups compared to the test randomly selected and sacrificed by euthanization using Indica for 0ne week. A significant (p<0.05) increase was observed Induction of Liver Injury Table 2 when compared to Table 1, reveals the potential hepa- control and control group. The significant increase (p<0.05) in Liver injury was induced in rats of group B – D by single oral to-healing effect of flacourtia Indica not necessarily in a dose de- pendent manner. administration with 260mg/kg body weight of AlCl3 respectively.

How to cite this article: Idoko A, Emmanuel U, Yakubu O, Ugwudike P, Patricia N. Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of 0074 Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats. Curr Trends Biomedical Eng & Biosci. 2019; 17(5): 555971. DOI: 10.19080/CTBEB.2019.17.555971. Current Trends in Biomedical Engineering & Biosciences

Table 2: Liver function assay of Rats after Induction with 260mg/kg/body weight AlCl3. Group TP(g/dl) ALB(g/dl) BIL (mg/dl) ALP(U/L) ALT(U/L) AST(U/L) A 25.95±12.82abc 6.27±1.67a 16.09±2.89ab 4702.05±976.99abc 36.5±3.54abc 38.5±3.54abc B 11.64±4.63a 6.35±1.79 10.54±2.15a 5301.04±97.98a 77.00±0.00a 71.5±6.34a C 6.87±2.16b 4.70±0.01a 15.47±4.87 5167.10±165.89b 71.00±8.49b 71.5±6.36b D 4.13±0.64c 5.16±1.15 10.14±0.99b 5000.20±135.11c 77.33±5.51c 80.33±7.51c Results are mean ± standard deviation, Values in the same column bearing similar superscripts are significantly different at P<0.05. (n=4). Key: A: Control Group; B: Test Control; C and D: Test groups. TP: Total Protein; ALB: Albumin; BIL: Bilirubin; ALP: Alkaline Phosphatase; ALT: Alanine Transaminase; AST: Aspartate Transaminase Table 3: Liver function assay of Rats after Treatment with 500mg/kg and 700mg/kg/body weight stem bark extracts of Flacourtia indica for 7days.

Control Test Control Test Groups Group A B C D TP(g/dl) 25.14±13.34abc 10.64±0.30a 2.54±0.82b 5.13±2.68c ALB(g/dl) 5.11±1.72a 5.38±1.19 5.43±0.19a 5.38±0.26 BIL(mg /dl) 13.53±8.29abc 10.99±1.93a 2.26±0.39b 2.03±0.63c ALP(U/L) 5202.60±74.16ab 5150.16±85.87 4583.16±430.11a 4650.60±66.36b ALT(U/L) 31.50±3.54abc 72.00±5.60a 47.75±3.69b 50.67±2.31c AST(U/L) 44.00±4.24abc 62.67±9.29a 33.00±5.19b 36.00±5.00c Results are mean ± standard deviation, Values in the same row bearing similar superscripts are significantly different at P<0.05. (n=4). Key: A: Control Group; B: Test Control; C and D: Test groups; TP: Total Protein; ALB: Albumin; BIL: Bilirubin; ALP: Alkaline Phosphatase; ALT: Alanine Transaminase; AST: Aspartate Transaminase Table 4 presents the blood glucose concentration of rats after induction with AlCl and after Treatment with stem bark extracts damaged hepatocyte (red arrow), degeneration of the hepatocyte 3 of liver showed massive influx of inflammatory cells (black arrow), of Flacourtia Indica. After administration (treatment), with cords and the affected hepatocytes are aligned in deformed cords Flacourtia Indica, the blood glucose concentrations of test groups which compresses the lumen of the sinuses. Zonal fatty changes occurred in the liver lobules, diffusely affecting the same zone. induction with AlCl in a dose dependent pattern, thus acerbating The fatty degeneration, vacuoles appeared in the cytoplasm (C and D) decreased3 significantly (p<0.05) compared to after induced hypoglycemia. around the nucleus, because the lipid content may be dissolved in Table 4: Blood Glucose Concentration (mg/dl) of Rats after Induction the course of embedding. The vacuoles are empty with absence of with AlCl3 after Treatment with stem bark extracts of Flacourcia Indica (Governor’s Plum). (white arrows). H&E. mag. 400X. After Induction After Treatment inflammatory cells (black arrows) and regenerated hepatocytes A 103.67±4.16 97.75±18.91 B 95.33±2.08a 101.67±4.93a C 96.00±2.00b 76.67±69.82b D 99.33±1.53c 75.00±6.08c Results are mean ± standard deviation, Values in the same row bearing similar superscripts are significantly different at P<0.05. (n=4). Key: A: Control Group; B: Test Control; C and D: Test groups Result of Histopathology Analysis The results of histopathological study of liver tissue of rats at induction (group A and B), after induction with AlCl3 and after treatment with F. indica ethanol stem bark extract (group C and D) as cross sections are shown in Figure 1 & 2. Photomicrograph of liver showed cytoplasm containing empty (black arrow) and the nucleus and then formed a signet-ring like appearance. H&E. fluid filled (red arrow) appearing vacuoles which pushed out mag. 400X (Figure 3). Photomicrograph of liver showed minor Figure 1: Group A Control Group Photomicrograph of liver distortion of the hepatic cords leading to enlarged sinusoids (black showed distinct architecture of kupffer cells (black arrow), cytoplasmic aligning (red arrow). And intact hepatocytes (blue arrow), also macrophages (red arrow) and focal necrosis (star) arrow). H&E. mag. X400. were also observed. H&E. mag. 100X (Figure 4). Photomicrograph

How to cite this article: Idoko A, Emmanuel U, Yakubu O, Ugwudike P, Patricia N. Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of 0075 Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats. Curr Trends Biomedical Eng & Biosci. 2019; 17(5): 555971. DOI: 10.19080/CTBEB.2019.17.555971. Current Trends in Biomedical Engineering & Biosciences

Discussion

indices in Table 2 of groups C and D, as compared to Table 3 was The significant increase that was observed in the liver function as a result of aluminium chloride administration. This result is

chloride is capable of inducing hepatic injury (hepatotoxicity), consistent with other researchers’ who reported that aluminium using a minimal dose of 34 mg/kg body weight administered in

Wistar albino rats of 0, 64mg/kg, 128mg/kg and 256mg/kg rats’ diet [35] and oral exposure in drinking water of 40 male body weight AlCl3 for 120days, respectively [9]. AlCl3 induced toxicity has been reported to have toxic effects on liver, kidney, biochemical dysfunction and general health challenge [13]. A

rats after induction with AlCl compared to after treatment with significant increase was seen3 in blood glucose concentration of Flacourtia indica (Table 4). This increase could have resulted from the inability of the liver to secret insulin owing from the hepatic

damage caused by AlCl3. The mechanism through which this was done was taught to be linked to hepatic-stress related release of Figure 2: Group B at Induction A/C/3. Photomicrograph of epinephrine, a factor inhibiting insulin secretion [36]. liver showed infiltration of mixed infiltrates in the sinusoid. The mid zonal region of the lobular architecture of the liver showed diffused fatty changes.

Figure 5: Group D after induction A/c/3(1). Figure 3: Group C after treatment with 500mg/kg of stem bark extract of Flacourtia indica (2). The potent inducement of liver injury by AlCl3 was supported by histopathology results (Figures 1, 2, 4 & 5). The underlying

mechanism through which AlCl3 induces hepatic damage, as hepatic toxicant, as shown by the histopathology results could be associated to fatty liver incidence as a result of accumulated triacylglycerols and lipoprotein [36]. The histopathological

distinct architecture of kupffer cells and cytoplasmic aligning results’ examination of liver tissues reveals intact hepatocytes, of the negative control group. Induction by AlCl3 in test groups

revealed several degrees of hepatic injuries including; infiltration of mixed infiltrates in the sinusoid, diffused fatty changes, hepatocyte, degeneration of the hepatocyte cords and the affected focal necrosis, massive influx of inflammatory cells, damaged hepatocytes are aligned in deformed cords which compresses the lumen of the sinuses (Figures 2, 4 & 5). Treatment with Flacourtia indica

’s ethanol extract stem bark with 500 mg/kg and 700 mg/ Figure 4: Group C after induction (1). kg in rat’s liver revealed regeneration of hepatocytes, absence of inflammation, with almost healed hepatic architecture (Figures How to cite this article: Idoko A, Emmanuel U, Yakubu O, Ugwudike P, Patricia N. Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of 0076 Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats. Curr Trends Biomedical Eng & Biosci. 2019; 17(5): 555971. DOI: 10.19080/CTBEB.2019.17.555971. Current Trends in Biomedical Engineering & Biosciences

3 & 6). This is also consistent with [28], supporting the claim behind the stability of blood glucose by Flacourtia indica could be that Flacourtia indica protects the liver against AlCl3 hepatic understood from the role of these mineral elements as cofactors to glycolytic enzyme especially hexokinase and phosphofructose absence of damaged and degenerated hepatocytes, necrosis and [17]. The blood glucose level stabilizing effects of Flacourtia indica damage in treated groups with healing features, typified by appears to be maintained by the constant furnishing of these mineral elements [37,38]. inflammation. Conflict of Interests Authors have declared that no competing interests exist. References 1. Alan F (2015) An overview of the liver: A series of fact sheets written in

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How to cite this article: Idoko A, Emmanuel U, Yakubu O, Ugwudike P, Patricia N. Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of 0078 Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats. Curr Trends Biomedical Eng & Biosci. 2019; 17(5): 555971. DOI: 10.19080/CTBEB.2019.17.555971.